To protect peptide pharmaceuticals against peptidases.

Area of Science:

• Biochemistry
• Biotechnology
• Medicinal Chemistry

Background:

• Peptide pharmaceuticals face challenges due to rapid in vivo breakdown.
• Stabilization is crucial for effective therapeutic application and delivery.

Purpose of the Study:

• To develop an innovative enzymatic method for stabilizing peptide pharmaceuticals.
• To create thioether-bridged peptides with enhanced therapeutic potential.

Main Methods:

• Combined D-amino acids and cyclization using an enzymatic approach in Lactococcus lactis.
• Engineered peptides with specific residues for thioether bridge formation.
• Utilized a lantibiotic leader peptide for enzyme-catalyzed synthesis and translocation.
• Tested the method on Luteïnizing Hormone Releasing Hormone (LHRH) analog QHWSYGCRPG.

Main Results:

• Successfully produced biologically thioether-bridged LHRH with N-terminal pyroglutamate and C-terminal amidation.
• The thioether LHRH isomer demonstrated superior stability and proteolytic resistance compared to natural LHRH.
• The thioether bridge formation was compatible with subsequent chemical and enzymatic modifications.

Conclusions:

• The enzymatic method enables stereo- and regiospecific generation of cyclized peptide pharmaceuticals.
• This approach significantly enhances the therapeutic potential of peptide drugs.
• The findings support broad applicability for developing more stable and effective peptide therapeutics.